1. Field of the Invention
This invention relates to the use of certain 3-substituted-2-oxindole-1-carboxamides and the pharmaceutically-acceptable base salts thereof for suppressing T-cell function in a mammal. The invention compounds and salts are useful in treating T-cell mediated autoimmune disorders. Such autoimmune disorders can be systemic or organ specific and include, but are not limited to, multiple sclerosis, systemic lupus erythematosus (SLE), type I diabetes, myasthenia gravis and chronic liver disease. The use of such compounds and salts comprise administering an effective amount thereof to a mammal.
2. General Background
Certain 3-substituted-2-oxindole-1-carboxamides of the formula ##STR2## and the pharmaceutically-acceptable base salts thereof wherein, inter alia, X is H, Cl or F; Y is H or Cl; and R is benzyl or thienyl are disclosed and claimed in U.S. Pat. No. 4,556,672 which is assigned to the assignee hereof. That patent discloses that those compounds, in addition to being useful as antiinflammatory and analgesic agents. are inhibitors of both cyclooxygenase (CO) and lipoxygenase (LO). The teachings thereof are incorporated herein by reference.
Certain autoimmune disorders of the systemic and organ specific type such as type I diabetes, chronic liver disease and myasthenia gravis, among others, are described in Autoimmunity: Basic Concepts; Systemic and Selected Organ Specific Diseases, Cruse, J. M. and Lewis, Jr., R. E., Eds., S. Karger, New York, 1985 at pages 51-71. The role of T-cell dysfunction and certain autoimmune disorders of the systemic and organ specific type such as systemic lupus erythematosus (SLE), among others, are disclosed in Bellanti, Joseph A., Immunology III, W. B. Saunders Co., Philadelphia (1985), Chapter 20, Part C., pages 409-446. The teachings of those references are incorporated herein by reference.
In copending U.S. patent application Ser. No. 181,131 entitled 3-Substituted-2-Oxindole-1-Carboxamides As Inhibitors of Interleukin-1 Biosynthesis, filed concurrently herewith and which is assigned to the assignee hereof, it is disclosed that the compounds of this invention do not inhibit lipoxygenase in the present of serum.
It has been reported that lipoxygenase metabolites play a role in T-lymphocyte mitogenesis. Baily, J. M., et al., Cellular Immunology, 67, 112-120 (1982); and Kelly, J. P., et al., J. Immunology, 122, 1563-1571 (1979). Further, certain inhibitors of cyclooxygenase have been reported to increase cell-mediated immunity, certain lipoxygenase inhibitors have been reported to inhibit cell-mediated immunity and certain cyclooxygenase and lipoxygenase inhibitors have been found to enhance cell-mediate immunity at lower concentrations and inhibit such immunity at higher concentrations. Leung, K. H., et al., Int. J. Immunopharmac., 4, 195-204 (1982).
Aspirin has been reported to suppress blastogenesis of lymphocytes. Crout, J. E., et al., N. E. J. Med., 292, 221-223 (1975). Further, IL-1 has been reported to augment T-cell activation and lymphokine release. See, Hanna, N. and Wood D. D., Adv. Inflammation Res., Vol. 12 (1988) at 11-14 and reference cited therein.
Until the invention herein, there was no report of use or intent to use the compounds or salts of this invention to suppress T-cell function independent of lipoxygenase inhibition and to treat T-cell mediated autoimmune disorders with such compounds nor any appreciation of their role in such treatments.